What are the common side effects and toxicities associated with cisplatin therapy?

Cisplatin Side Effects and Toxicities

Cisplatin causes severe, dose-limiting toxicities across multiple organ systems, with nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression being the most clinically significant adverse effects that directly impact patient morbidity and quality of life. 1

Major Toxicities

Nephrotoxicity (Renal Toxicity)

• Cumulative renal toxicity is the most severe dose-limiting toxicity associated with cisplatin, occurring in approximately 30-67% of patients at any grade 2, 1
• Grade ≥3 renal toxicity occurs in 0-2% of patients 2
• Renal tubular damage leads to secondary electrolyte disturbances including hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia 1
• Tetany can occur in patients with hypocalcemia and hypomagnesemia 1
• Cisplatin should not be administered if serum creatinine is ≥1.5 mg/100 mL or BUN is ≥25 mg/100 mL 1
• Intensive hydration with 1-2 liters of fluid for 8-12 hours before cisplatin, followed by adequate hydration for 24 hours after, is the mainstay of prevention 1, 3

Ototoxicity (Hearing Loss)

• Ototoxicity occurs in up to 31% of patients after a single 50 mg/m² dose, manifesting as tinnitus and/or high-frequency hearing loss (4,000-8,000 Hz) 1
• In children, the prevalence is particularly high at 40-60% 1
• The toxicity is permanent and progressive, potentially worsening even after treatment cessation 2
• Decreased ability to hear normal conversational tones may occur; deafness after initial dose has been reported 1
• Vestibular toxicity has also been documented 1
• Audiometric monitoring should be performed prior to initiation, before each subsequent dose, and for several years post-therapy 1
• Risk factors include: age <5 years, cumulative dose, concurrent cranial irradiation, concomitant ototoxic drugs (aminoglycosides, vancomycin), renal impairment, and genetic variants (e.g., TPMT gene) 1, 4
• For non-metastatic hepatoblastoma, systemic sodium thiosulfate is strongly recommended for ototoxicity prevention 2

Neurotoxicity (Peripheral Neuropathy)

• Peripheral neuropathies occur in approximately 10% of patients (any grade), with grade ≥3 occurring in 0-3% 2
• Neuropathies typically develop after prolonged therapy (4-7 months), but can occur after a single dose 1
• Symptoms may begin 3-8 weeks after the last cisplatin dose and may be irreversible in some patients 1
• Cisplatin therapy should be discontinued when neurologic symptoms are first observed, though neuropathy may progress further even after stopping 1
• Elderly patients are more susceptible to peripheral neuropathy 1
• Additional neurologic manifestations include: Lhermitte's sign, dorsal column myelopathy, autonomic neuropathy, loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) 1
• Muscle cramps occur with high cumulative doses and advanced neuropathy stages 1

Myelosuppression (Bone Marrow Suppression)

• Myelosuppression occurs in 25-30% of patients, with more pronounced effects at doses >50 mg/m² 1
• Nadirs in platelets and leukocytes occur between days 18-23 (range 7.5-45), with most patients recovering by day 39 (range 13-62) 1
• Anemia (≥2 g hemoglobin/100 mL decrease) occurs at similar frequency and timing as leukopenia and thrombocytopenia 1
• Fever and infection have been reported in neutropenic patients, with potential fatalities due to infection-related complications 1
• Elderly patients may be more susceptible to myelosuppression 1
• Coombs' positive hemolytic anemia has been reported; further treatment may increase hemolysis risk 1
• Repeat courses should not be given until platelets ≥100,000/mm³ and WBC ≥4,000/mm³ 1

Gastrointestinal Toxicity

• Marked nausea and vomiting occur in almost all patients and may be so severe that treatment must be discontinued 1
• Symptoms begin within 1-4 hours after treatment and last up to 24 hours 1
• Varying degrees of vomiting, nausea, and/or anorexia may persist for up to 1 week after treatment 1
• Delayed nausea and vomiting (≥24 hours after chemotherapy) occurs even in patients with complete emetic control on the day of therapy 1
• Optimal prevention requires aggressive four-drug prophylaxis: NK1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone, and olanzapine 3
• Diarrhea has also been reported 1

Additional Significant Toxicities

Ocular Toxicity

• Optic neuritis, papilledema, and cerebral blindness have been reported with standard doses 1
• Improvement or total recovery usually occurs after discontinuing cisplatin 1
• Blurred vision and altered color perception (particularly blue-yellow axis loss) occur with higher doses or greater frequency than recommended 1

Vascular Toxicity

• Vascular events include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome), and cerebral arteritis 1
• Raynaud's phenomenon occurs in patients treated with bleomycin and vinblastine combinations with or without cisplatin 1

Hyperuricemia

• Occurs at similar frequency as BUN and creatinine increases, more pronounced at doses >50 mg/m² 1
• Peak uric acid levels occur 3-5 days after dosing 1
• Allopurinol therapy effectively reduces uric acid levels 1

Anaphylactic-Like Reactions

• Consist of facial edema, wheezing, tachycardia, and hypotension within minutes of administration 1
• More common in patients previously exposed to cisplatin 1
• Patients should be observed carefully with supportive equipment and medications (epinephrine, corticosteroids, antihistamines) immediately available 1

Hepatotoxicity

• Transient elevations of liver enzymes (especially SGOT) and bilirubin have been reported 1

Critical Clinical Considerations

Absolute Contraindications to Cisplatin

The following represent absolute contraindications based on consensus guidelines 2:

• Poor performance status (ECOG ≥3)
• Impaired renal function (creatinine clearance <50 mL/min)
• Preexisting hearing loss or grade ≥2 tinnitus
• Grade ≥2 peripheral neuropathy
• Severe marrow, hepatic, respiratory, cardiovascular, or metabolic dysfunction
• First trimester of pregnancy
• Allergy to platinum compounds

Age-Related Considerations

• Older age is associated with increased risk of ototoxicity, neurotoxicity, and nephrotoxicity 4
• Elderly patients are more susceptible to myelosuppression and peripheral neuropathy 1
• Children are particularly vulnerable to ototoxicity with prevalence of 40-60% 1

Long-Term Toxicity Concerns

• Cisplatin toxicities can be permanent, progressive, and impact long-term quality of life in cancer survivors 5, 6
• Late effects include persistent neuropathy, hearing loss, cardiovascular complications, secondary malignancies, hypogonadism, and infertility 6
• Circulating platinum levels and cumulative cisplatin dose correlate with long-term toxicity risk 6

Prevention of Overdose

• Doses >100 mg/m²/cycle once every 3-4 weeks are rarely used 1
• Care must be taken to avoid confusion with carboplatin or prescribing errors that fail to differentiate daily doses from total dose per cycle 1
• Acute overdosage can result in kidney failure, liver failure, deafness, ocular toxicity (including retinal detachment), significant myelosuppression, intractable nausea/vomiting, neuritis, and death 1